Abstract It is well known that noncoding RNAs (ncRNAs) cannot encode proteins, but they can play important regulatory roles in tumors by combining with proteins, RNAs, and DNAs. As more and more studies reveal the important roles and underlying mechanisms of long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) in cancer, their huge application potential in cancer therapy cannot be ignored. For example, lncRNAs can be involved in tumor‐related signal transduction pathways, cell cycle control, DNA damage, epigenetic regulation, and microRNA control. A group of studies confirmed that abnormal expression of lncRNAs can affect cancer progression. Furthermore, as covalently closed continuous circular ncRNAs, many recent studies have shown that circRNAs have regulatory effects and other important biological significances in cancer. Interestingly, circRNAs were found to have translational functions. This has greatly attracted people's attention to circRNAs research. In this review, we introduce the important roles of lncRNAs and circRNAs in some representative cancers, respectively. Furthermore, we focus on the biological functions and important clinical therapeutic implications of lnRNAs and circRNAs in neuroblastoma. Our review also focuses on providing rationale and relevant references for novel biomarkers for neuroblastoma diagnosis, prognosis, and treatment.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/mco2.141

LncRNAs and CircRNAs in cancer

The remarkable growth of genome-wide association studies (GWAS) has created a critical need to experimentally validate the disease-associated variants, 90% of which involve non-coding variants.To determine how the field is addressing this urgent need, we performed a comprehensive literature review identifying 36,676 articles. These were reduced to 1454 articles through a set of filters using natural language processing and ontology-based text-mining. This was followed by manual curation and cross-referencing against the GWAS catalog, yielding a final set of 286 articles.We identified 309 experimentally validated non-coding GWAS variants, regulating 252 genes across 130 human disease traits. These variants covered a variety of regulatory mechanisms. Interestingly, 70% (215/309) acted through cis-regulatory elements, with the remaining through promoters (22%, 70/309) or non-coding RNAs (8%, 24/309). Several validation approaches were utilized in these studies, including gene expression (n = 272), transcription factor binding (n = 175), reporter assays (n = 171), in vivo models (n = 104), genome editing (n = 96) and chromatin interaction (n = 33).This review of the literature is the first to systematically evaluate the status and the landscape of experimentation being used to validate non-coding GWAS-identified variants. Our results clearly underscore the multifaceted approach needed for experimental validation, have practical implications on variant prioritization and considerations of target gene nomination. While the field has a long way to go to validate the thousands of GWAS associations, we show that progress is being made and provide exemplars of validation studies covering a wide variety of mechanisms, target genes, and disease areas. 

/pdf/the-landscape-of-gwas-validation-systematic-review-26r32gpu.pdf

The landscape of GWAS validation; systematic review identifying 309 validated non-coding variants across 130 human diseases

Cancer is driven by both germline and somatic genetic changes. Efforts have been devoted to characterizing essential genetic variations in cancer initiation and development. Most attention has been given to mutations in protein-coding genes and associated regulatory elements such as promoters and enhancers. The development of sequencing technologies and in silico and experimental methods has allowed further exploration of cancer predisposition variants and important somatic mutations in noncoding RNAs, mainly for long noncoding RNAs and microRNAs. Association studies including GWAS have revealed hereditary variations including SNPs and indels in lncRNA or miRNA genes and regulatory regions. These mutations altered RNA secondary structures, expression levels, and target recognition and then conferred cancer predisposition to carriers. Whole-exome/genome sequencing comparing cancer and normal tissues has revealed important somatic mutations in noncoding RNA genes. Mutation hotspots and somatic copy number alterations have been identified in various tumor-associated noncoding RNAs. Increasing focus and effort have been devoted to studying the noncoding region of the genome. The complex genetic network of cancer initiation is being unveiled. This article is categorized under: RNA in Disease and Development > RNA in Disease. 

Noncoding RNA mutations in cancer

Fatty acids are involved in the development and progression of colorectal cancer (CRC). However, genetic effects of fatty acid biosynthesis pathway on CRC outcome are unclear. Cox regression model was used to evaluate genetic effects on CRC overall survival (OS) and progression-free survival (PFS), accompanied by calculating hazard ratios (HRs) and confidence intervals (CIs). Differential expression analysis, expression quantitative trait loci analysis, dual-luciferase reporter assay and chromatin immunoprecipitation assay were performed to explore the genetically biological mechanism. The rs10838164 C>T in HSD17B12 was significantly associated with an increased risk of death and progression of CRC (OS, HR = 2.12, 95% CI = 1.40-3.22, P = 4.03 × 10-4 ; PFS, HR = 1.64, 95% CI = 1.11-2.44, P = 1.35 × 10-2 ), of which T allele could increase HSD17B12 expression (P = 1.78 × 10-11 ). Subsequently, the functional experiments indicated that rs10838164 T allele could not only enhance the binding affinity of transcription factor YY1 to HSD17B12 region harbouring rs10838164 but also promote the transcriptional activity of HSD17B12, which was significantly up-regulated in colorectal tumour tissues. Our findings suggest that genetic variants in fatty acid biosynthesis pathway play an important role in CRC outcome.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/jcmm.16026

Functional genetic variant of HSD17B12 in the fatty acid biosynthesis pathway predicts the outcome of colorectal cancer.

lncMGPF is a novel positive regulator of myogenic differentiation, muscle growth and regeneration in mouse, pig, and human. But whether natural mutations within lncMGPF gene regulate animal meat production traits is unclear. In this study, ten single nucleotide polymorphisms (SNPs) of pig lncMGPF (plncMGPF) gene were identified among commercial pig breeds and Chinese local pig breeds. These SNPs are highly linked and constructed into multiple haplotypes, and haplotype ATTCATGTTC (H1) mainly exists in commercial pig breeds while haplotype GCCTGCACCT (H3) is more frequent in Chinese local pig breeds. Association analysis indicated that all SNPs are significantly associated with the backfat thickness and loin muscle area (P < 0.05), respectively, and homologous H1 individuals have higher loin muscle area and lower backfat thickness than H3 pigs. Bioinformatics and functional analysis showed that haplotype H1 has a longer half-life and more stable RNA secondary structure than haplotype H3. plncMGPF haplotype H1 has stronger effects on pig primary myogenic progenitor cells differentiation and muscle growth than haplotype H3. Further experiments showed that two SNPs (rs81403974 and rs325492834) function together to confer plncMGPF stability and function. Our observation suggested that the SNPs in lncMGPF can change the RNA stabilities and lncMGPF function, thereby affecting the porcine meat production traits.

/pdf/single-nucleotide-polymorphisms-of-porcine-lncmgpf-regulate-t0u4nlgbhe.pdf

Single Nucleotide Polymorphisms of Porcine lncMGPF Regulate Meat Production Traits by Affecting RNA Stability.

The biological effects of susceptibility loci are rarely reported in gastric tumorigenesis. We conducted a large-scale cross-ancestry genetic study in 18,852 individuals and identified the potential causal variant rs3850997 T>G at 16p13 significantly associated with a decreased risk of gastric cancer [odds ratio (OR) = 0.87, 95% confidence interval (CI) = 0.83 to 0.91, P = 2.13 × 10-9]. This risk effect was mediated through the mapped long noncoding RNA GCLET (Gastric Cancer Low-Expressed Transcript; ORindirect = 0.987, 95% CI = 0.975 to 0.999, P = 0.018). Mechanistically, rs3850997 exerted an allele-specific long-range regulatory effect on GCLET by affecting the binding affinity of CTCF. Furthermore, GCLET increased FOXP2 expression by competing with miR-27a-3p, and this regulation remarkably affected in vitro, in vivo, and clinical gastric cancer phenotypes. The findings highlight the genetic functions and implications for the etiology and pathology of cancers.

https://advances.sciencemag.org/content/advances/6/21/eaay5525.full.pdf

Remote modulation of lncRNA GCLET by risk variant at 16p13 underlying genetic susceptibility to gastric cancer

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Remote modulation of lncRNA GCLET by risk variant at 16p13 underlying genetic susceptibility to gastric cancer